Submissions for variant NM_172107.4(KCNQ2):c.1627G>A (p.Val543Met)

gnomAD frequency: 0.00001  dbSNP: rs794727134

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000724023	SCV000226184	uncertain significance	not provided	2018-06-25	criteria provided, single submitter	clinical testing
GeneDx	RCV000724023	SCV000241509	uncertain significance	not provided	2018-03-12	criteria provided, single submitter	clinical testing	The V543M variant has been previously reported in an individual with benign familial neonatal seizures; the variant was also identified in the affected father and 2 paternal aunts (Lee et al., 2017). Functional studies demonstrate the V543M variant causes a mild electrophysiological change in channel function compared to wild type (Lee et al., 2017). Missense variants in nearby residues have been reported in the Human Gene Mutation Database in individuals with with KCNQ2-related disorders (Stenson et al., 2014). The V543M variant is observed in 1/108796 (0.001%) alleles from individuals of European background (Lek et al., 2016). However, the V543M variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic variant or a rare benign variant.
Ambry Genetics	RCV002317007	SCV000851155	likely pathogenic	Inborn genetic diseases	2017-03-01	criteria provided, single submitter	clinical testing	The p.V543M variant (also known as c.1627G>A), located in coding exon 14 of the KCNQ2 gene, results from a G to A substitution at nucleotide position 1627. The valine at codon 543 is replaced by methionine, an amino acid with highly similar properties. This variant has been determined to be the result of a de novo mutation or germline mosaicism in one family with an isolated case of KCNQ2-related seizure disorder. This amino acid position is well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Fulgent Genetics, Fulgent Genetics	RCV000765493	SCV000896789	uncertain significance	Seizures, benign familial neonatal, 1; Developmental and epileptic encephalopathy, 7	2018-10-31	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV001240137	SCV001413061	pathogenic	Early infantile epileptic encephalopathy with suppression bursts	2023-08-03	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects KCNQ2 function (PMID: 28399683). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 194446). This missense change has been observed in individuals with clinical features of benign familial neonatal-infantile seizures or early infantile epileptic encephalopathy (PMID: 28399683, 29056246, 31199083; Invitae). It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs794727134, gnomAD 0.0009%). This sequence change replaces valine, which is neutral and non-polar, with methionine, which is neutral and non-polar, at codon 543 of the KCNQ2 protein (p.Val543Met).
Clinical Molecular Genetics Laboratory, Johns Hopkins All Children's Hospital	RCV000781975	SCV000920430	likely pathogenic	Seizures, benign familial neonatal, 1	2016-11-15	no assertion criteria provided	clinical testing
Centre de Biologie Pathologie Génétique, Centre Hospitalier Universitaire de Lille	RCV001527628	SCV001738739	pathogenic	Developmental and epileptic encephalopathy, 7	2020-01-01	no assertion criteria provided	clinical testing
Channelopathy-Associated Epilepsy Research Center	RCV003315309	SCV004015093	not provided	Complex neurodevelopmental disorder		no assertion provided	literature only